Release of Oxytocin in the Rat Central Amygdala Modulates Stress-Coping Behavior and the Release of Excitatory Amino Acids

Abstract

Previous experiments have indicated that the release of oxytocin (OXT) occurs in various hypothalamic and extrahypothalamic brain areas. In the present study, we investigated in male rats whether swim stress triggers the release of OXT in the central amygdala (CeA), a key area in processing emotions and stress responses. Further, we examined the physiological significance of OXT released within the CeA for behavioral responses during forced swimming as well as effects on the local release of selected amino acids including glutamate, aspartate, arginine, taurine, and GABA, which are thought to modulate processing of emotions. Exposure to a 10-min forced swimming session caused a significant increase in OXT release (200%, po0.01) within, but not outside, the CeA as monitored by microdialysis. Administration of the OXT receptor antagonist des-Gly-NH 2 d(CH 2 ) 5 (Tyr(Me) 2 Thr 4 )OVT via inverse microdialysis into the amygdala before and during exposure to swimming reduced the floating time by 55% (po0.05) and increased the swimming time by 29% (po0.05) indicative of a more active stress-coping strategy. Simultaneously, local administration of the OXT receptor antagonist caused a significant increase in the stress-induced release of the excitatory amino acids glutamate and aspartate, whereas the basal release of these amino acids remained unchanged. Taken together, these findings demonstrate a significant activation of the oxytocinergic system in the CeA in response to swim stress. Furthermore, our data indicate that OXT receptor-mediated mechanisms within the amygdala are involved in the generation of passive stress-coping strategies, which might be mediated at least in part via its inhibitory influence on the local release of excitatory amino acids during stress.

Prefrontal/Amygdalar System Determines Stress Coping Behavior Through 5-HT/GABA Connection

“…Here evidence is reported of a brain system which, through modulation of GABA in the amygdala prefrontal cortical 5-HT, controls behavioral responses to stressful experiences sustaining immobility in the forced swimming paradigm that models depressive-like outcomes in rodents (Ebner et al, 2005(Ebner et al, , 2008Singewald et al, 2011). It was first demonstrated that, in mice, a stressful experience such as restraint induces a time-dependent increase of 5-HT output in the mpFC and of GABA in the BLA, in agreement with previous reports (Reznikov et al, 2009;Pascucci et al, 2009), and that selective depletion of cortical 5-HT canceled out these stress-induced responses, thus pointing to a controlling role of GABAergic transmission in amygdala by prefrontal 5-HT during stress.…”

“…Although depression is seen largely as a dysfunction in monoamine neurotransmission and all antidepressant strategies focus largely on monoamines, strong clinical and preclinical evidence implicates dysfunction of the GABAergic system in depression (Krystal et al, 2002). In rodents, the amygdala has been shown to be involved in depressive-like behavior in the FST, at least in part through GABA release (Ebner et al, 2005;Briones-Aranda et al, 2005). Different studies described antidepressant effects of the GABAb receptor agonist baclofen in FST (Cryan and Kaupmann, 2005), conceivably through presynaptic GABAb receptor activation leading to decrease of GABA release (Rea et al, 2005).…”

“…On the basis of results from experiment 1 showing a prefrontal 5-HT-amygdalar GABA circuitry in response to stress, it was investigated if this system is involved also in controlling coping behavior in the FST. First, the effect of bilateral prefrontal selective 5-HT depletion in mpFC and L-allylglycine (1 mM) bilateral infusion in BLA were assessed on behavioral outcomes in the FST, a well-known experimental condition commonly used to investigate stress-related behavior and to model depressive-like behavior in rodents (Porsolt et al, 1977;Valentino et al, 2010;Ebner et al, 2005). Selective bilateral 5-HT depletion in mpFC (Sham group (n ¼ 8) 293.18±6.6 s, 5-HT-depleted group (n ¼ 8) 122.19 ± 13.3 s, F 1.14 ¼ 132.2, Po0.01) or bilateral BLA L-allylglycine infusion (bilateral BLA CSF (n ¼ 6) 307.5±16.1 s, bilateral BLA L-allylglycine group (n ¼ 7) 135.2 ± 8.6 s, F 1.11 ¼ 95.79, Po0.01) significantly reduced immobility.…”

“…The mpFC is thought to have a critical role in regulating amygdala-mediated arousal in response to emotionally salient stimuli, and the 5-hydroxytryptamine (5-HT) system within the mpFC represents a potential molecular mechanism through which the mpFC modulates corticolimbic circuitry (Fisher et al, 2009). Moreover, manipulation of GABAergic transmission within the basolateral amygdala (BLA) has a critical influence both on behavioral and emotional sequelae resulting from stress (Martijena et al, 2002;Ebner et al, 2005). This suggests that 5-HT transmission in the mpFC is likely to engage GABA in the amygdala in stressful situations in order to determine coping outcomes.…”

“…This suggests that 5-HT transmission in the mpFC is likely to engage GABA in the amygdala in stressful situations in order to determine coping outcomes. Here, using mice, it was attempted to assess whether amygdalar GABA regulation by prefrontal cortical 5-HT is a common neural substrate involved in processing stressful experiences and in determining active or passive coping behavior during forced swimming (Ebner et al, 2005(Ebner et al, , 2008Singewald et al, 2011). In particular, it was investigated whether 5-HT in prefrontal cortex is involved in brain response to uncontrollable stress through its modulating action on GABA in amygdala and whether these brain areas are part of a neural system necessary for the implementation of adaptive coping strategies.…”